The present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A2 enzymes.
Leukotrienes and prostaglandins are important mediators of inflammation, each of which classes contributes to the development of an inflammatory response in a different way. Leukotrienes recruit inflammatory cells such as neutrophils to an inflamed site, promote the extravasation of these cells and stimulate release of superoxide and proteases which damage the tissue. Leukotrienes also play a pathophysiological role in the hypersensitivity experienced by asthmatics [See, e.g. B. Samuelson et al., Science, 237:1171-76 (1987)]. Prostaglandins enhance inflammation by increasing blood flow and therefore infiltration of leukocytes to inflamed sites. Prostaglandins also potentiate the pain response induced by stimuli.
Prostaglandins and leukotrienes are unstable and are not stored in cells, but are instead synthesized [W. L. Smith, Biochem. J., 259:315-324 (1989)] from arachidonic acid in response to stimuli. Prostaglandins are produced from arachidonic acid by the action of COX-1 and COX-2 enzymes. Arachidonic acid is also the substrate for the distinct enzyme pathway leading to the production of leukotrienes.
Arachidonic acid which is fed into these two distinct inflammatory pathways is released from the sn-2 position of membrane phospholipids by phospholipase A2 enzymes (hereinafter PLA2). The reaction catalyzed by PLA2 is believed to represent the rate-limiting step in the process of lipid mediated biosynthesis and the production of inflammatory prostaglandins and leukotrienes. When the phospholipid substrate of PLA2 is of the phosphotidyl choline class with an ether linkage in the sn-1 position, the lysophospholipid produced is the immediate precursor of platelet activating factor (hereafter called PAF), another potent mediator of inflammation [S. I. Wasserman, Hospital Practice, 15:49-58 (1988)].
Most anti-inflammatory therapies have focussed on preventing production of either prostglandins or leukotrienes from these distinct pathways, but not on all of them. For example, ibuprofen, aspirin, and indomethacin are all NSAIDs which inhibit the production of prostaglandins by COX-1/COX-2, but have no effect on the inflammatory production of leukotrienes from arachidonic acid in the other pathways. Conversely, zileuton inhibits only the pathway of conversion of arachidonic acid to leukotriense, without affecting the production of prostaglandins. None of these widely-used anti-inflammatory agents affects the production of PAF.
Consequently the direct inhibition of the activity of PLA2 has been suggested as a useful mechanism for a therapeutic agent, i.e., to interfere with the inflammatory response. [See, e.g., J. Chang et al, Biochem. Pharmacol., 36:2429-2436 (1987)].
A family of PLA2 enzymes characterized by the presence of a secretion signal sequenced and ultimately secreted from the cell have been sequenced and structurally defined. These secreted PLA2s have an approximately 14 kD molecular weight and contain seven disulfide bonds which are necessary for activity. These PLA2s are found in large quantities in mammalian pancreas, bee venom, and various snake venom. [See, e.g., references 13-15 in Chang et al, cited above; and E. A. Dennis, Drug Devel. Res., 10:205-220 (1987).] However, the pancreatic enzyme is believed to serve a digestive function and, as such, should not be important in the production of the inflammatory mediators whose production must be tightly regulated.
The primary structure of the first human non-pancreatic PLA2 has been determined. This non-pancreatic PLA2 is found in platelets, synovial fluid, and spleen and is also a secreted enzyme. This enzyme is a member of the aforementioned family. [See, J. J. Seilhamer et al, J. Biol. Chem., 264:5335-5338 (1989); R. M. Kramer et al, J. Biol. Chem., 264:5768-5775 (1989); and A. Kando et al, Biochem. Biophys. Res. Comm., 163:42-48 (1989)]. However, it is doubtful that this enzyme is important in the synthesis of prostaglandins, leukotrienes and PAF, since the non-pancreatic PLA2 is an extracellular protein which would be difficult to regulate, and the next enzymes in the biosynthetic pathways for these compounds are intracellular proteins. Moreover, there is evidence that PLA2 is regulated by protein kinase C and G proteins [R. Burch and J. Axelrod, Proc. Natl. Acad. Sci. U.S.A., 84:6374-6378 (1989)] which are cytosolic proteins which must act on intracellular proteins. It would be impossible for the non-pancreatic PLA2 to function in the cytosol, since the high reduction potential would reduce the disulfide bonds and inactivate the enzyme.
A murine PLA2 has been identified in the murine macrophage cell line, designated RAW 264.7. A specific activity of 2 mols/min/mg, resistant to reducing conditions, was reported to be associated with the approximately 60 kD molecule. However, this protein was not purified to homogeneity. [See, C. C. Leslie et al, Biochem. Biophys. Acta., 963:476-492 (1988)]. The references cited above are incorporated by reference herein for information pertaining to the function of the phospholipase enzymes, particularly PLA2.
A cytosolic phospholipase A2 (hereinafter xe2x80x9ccPLA2xe2x80x9d) has also been identified and cloned. See, U.S. Pat. Nos. 5,322,776 and 5,354,677, which are incorporated herein by reference as if fully set forth. The enzyme of these patents is an intracellular PLA2 enzyme, purified from its natural source or otherwise produced in purified form, which functions intracellularly to produce arachidonic acid in response to inflammatory stimuli.
It is now desirable to identify pharmaceutically useful compounds which inhibit the actions of these phospholipase enzymes for use in treating or preventing inflammatory conditions, particularly where inhibition of production of prostaglandins, leukotrienes and PAF are all desired results. There remains a need in the art for an identification of such anti-inflammatory agents for therapeutic use in a variety of disease states.
Numerous pieces of evidence have supported the central role of cPLA2 in lipid mediator biosynthesis: cPLA2 is the only enzyme which is highly selective for phospholipids containing arachidonic acid in the sn-2 position (Clark et al., 1991, 1995; Hanel and Gelb, 1993); activation of cPLA2 or its increased expression have been linked with increased leukotriene and prostaglandin synthesis (Lin et al., 1992a, 1992b, 1993); and following activation, cPLA2 translocates to the nuclear membrane, where it is co-localized with the cyclooxygenase and lipoxygenase that metabolize arachidonate to prostaglandins and leukotrienes (Schievella et al., 1995; Glover et al., 1995). Although these data are compelling, the most definitive evidence for the central role of cPLA2 in eicosanoid and PAF production came from mice made deficient in cPLA2 through homologous recombination (Uozumi et al., 1997; Bonventre et al., 1997). Peritoneal macrophages derived from these animals failed to make leukotrienes, prostaglandins, or PAF. The cPLA2 deficient mice have also been informative of the role of cPLA2 in disease, since these mice are resistant to bronchial hyperreactivity in an anaphylaxis model used to mimic asthma (Uozumi et al., 1997). Thus, despite the size of the phospholipase A2 superfamily, cPLA2 is essential for prostaglandin, leukotriene, and PAF production.
Clark, J. D., Lin, L.-L., Kriz, R. W., Ramesha, C. S., Sultzman, L. A., Lin, A. Y., Milona, N., and Knopf, J. L. (1991). A novel arachidonic acid-selective cytosolic PLA2 contains a Ca2+-dependent translocation domain with homology to PKC and GAP. Cell 65,1043-1051. Hanel, A. M., and Gelb, M. H. (1993). Processive interfacial catalysis by mammalian 85-kilodalton phospholipase A2 enzymes on product-containing vesicles: application to the determination of substrate preferences. Biochemistry 32, 5949-5958.
Lin, L.-L., Lin, A. Y., and DeWitt, D. L. (1992a) IL-1_ induces the accumulation of cPLA2 and the release of PGE2 in human fibroblasts. J. Biol. Chem. 267, 23451-23454. Lin, L.-L., Lin, A. Y., and Knopf, J. L. (1992b) Cytosolic phospholipase A2 is coupled to hormonally regulated release of arachidonic acid. Proc. Natl. Acad. Sci. USA 89, 6147-6151. Lin, L.-L., Wartmann, M., Lin, A. Y., Knopf, J. L., Seth, A., and Davis, R. J. (1993) cPLA2 is phosphorylated and activated by MAP kinase. Cell 72, 269-278.
Glover, S., de Carvalho, M., Bayburt, T., Jonas, M., Chi, E., Leslie, E., and Gelb, M. (1995) Translocation of the 85-kDa phospholipase A2 from cytosol to the nuclear envelope in rat basophilic leukemia cells stimulated with calcium ionophore or IgE/antigen. J. Biol. Chem. 270, 15359-15367. Schievella, A. R., Regier, M. K., Smith, W. L., and Lin, L.-L. (1995). Calcium-mediated translocation of cytosolic phospholipase A2 to the nuclear envelope and endoplasmic reticulum. J. Biol. Chem. 270, 30749-30754.
Uozumi, N., Kume, K., Nagase, T., Nakatani, N., Ishii, S., Tashiro, F., Komagata, Y., Maki, K., Ikuta, K., Ouchi, Y., Miyazaki, J.-i., and Shimizu, T. (1997). Role of cytosolic phospholipase A2 in allergic response and parturition. Nature 390, 618-622. Bonventre, J. V., Huang, Z., Reza Taheri, M., O""Leary, E., Li, E., Moskowitz, M. A., and Sapirstein, A. (1997) Reduced fertility and postischaeric brain injury in mice deficient in cytosolic phospholipase A2. Nature 390, 622-625.
Compounds of this invention have the following formulae: 
wherein:
R1 and R1, are independently selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C10 alkyl, preferably xe2x80x94Sxe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, phenyl, xe2x80x94O-phenyl, xe2x80x94S-phenyl, benzyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl; or a ring moiety of the groups a), b) or c), below, directly bonded to the indole ring or bonded to the indole ring by a xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94(CH2)nxe2x80x94 bridge;
a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3; or
b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH; or
c) a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH; or
d) a moiety of the formulae: 
Z is O or S;
R6 is selected from the relevant members of the group H, xe2x80x94CF3, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, phenyl, xe2x80x94O-phenyl, xe2x80x94S-phenyl, benzyl, xe2x80x94O-benzyl, or xe2x80x94S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
R7 is selected from xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(C1-C6 alkyl)2, xe2x80x94(CH2)xe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94CF3, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, xe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94Nxe2x80x94(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, quinolyl, (CH2)nphenyl, phenyl, xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, adamantyl, or morpholinyl, xe2x80x94(CH2)n-phenyl-O-phenyl, xe2x80x94(CH2)n-phenyl-CH2-phenyl, xe2x80x94(CH2)n-O-phenyl-CH2-phenyl, xe2x80x94(CH2)n-phenyl-(Oxe2x80x94CH2-phenyl)2, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94CF3,CO2H, or xe2x80x94OH; or
a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH; or
c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH;
n is an integer from 0 to 3;
R2 is selected from H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OH, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from xe2x80x94COOH, xe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, (CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94COOH, xe2x80x94(CH2)n-tetrazole, 
xe2x80x83or a moiety selected from the formulae xe2x80x94L1xe2x80x94M1;
wherein L1 is a bridging or linking moiety selected from a chemical bond, xe2x80x94(CH2)nxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94, xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94, xe2x80x94C(O)xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94(CH2)nxe2x80x94, xe2x80x94C(Z)xe2x80x94NHxe2x80x94SO2xe2x80x94, xe2x80x94C(Z)xe2x80x94NHxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SOxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94Oxe2x80x94;
n is an integer from 0 to 3
M1 is selected from the group of xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, 
R8, in each appearance, is independently selected from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NH2, 
R9 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94Oxe2x80x94CH2xe2x80x94Cxe2x95x90Cxe2x80x94COOH, xe2x80x94Oxe2x80x94Cxe2x95x90Cxe2x80x94CH2xe2x80x94COOH, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94Nxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94C(O)xe2x80x94Nxe2x80x94(CH2)nxe2x80x94COOH;
R10 is selected from the group of H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94(C1-C6 alkyl)xe2x80x94(OH)n, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94C(O)xe2x80x94Nxe2x80x94(C1-C6 alkyl)-(OH)2, 
R11 is selected from H, C1-C6 lower alkyl, C1-C6 cycloalkyl, xe2x80x94CF3, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, 
xe2x80x83with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R3, L1, M, R8, R9, R10, and/or R11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: xe2x80x94C(O)xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NH2, 
n is an integer from 0 to 3;
R4 is selected from H, xe2x80x94CF3, C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, xe2x80x94C1-C6 alkyl-C3xe2x80x94C10 cycloalkyl, xe2x80x94CHO, halogen, or a moiety of the formula xe2x80x94L2xe2x80x94M2:
L2 indicates a linking or bridging group of the formulae xe2x80x94(CH2)nxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, C(O)C(O)X, or xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(CH2)n;
where X is O or N
n is an integer from 0 to 3
M2 is selected from:
a) H, the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH; or
d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 0 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 0 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH;
R5 is selected from C1-C6 lower alkyl, C1-C6 lower alkoxy, xe2x80x94(CH2)nxe2x80x94C3-C10 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C3-C10 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94C1-C10 cycloalkyl, or the groups of:
a) xe2x80x94(CH2)n-phenyl-O-phenyl, xe2x80x94(CH2)n-phenyl-CH2-phenyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94phenyl-CH2-phenyl, xe2x80x94(CH2)n-phenyl-(Oxe2x80x94CH2-phenyl)2, xe2x80x94CH-phenyl-C(O)-benzothiazole or a moiety of the formulae: 
xe2x80x83wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2,
Y is C3-C6 cycloalkyl, phenyl, biphenyl, each optionally substituted by from 1 to 3 groups selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or by one phenyl ring, the phenyl ring being optionally substituted by by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3; or
b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH; or
c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH;
d) a moiety of the formulae xe2x80x94(CH2)nxe2x80x94A, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94A, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94A, wherein A is the moiety: 
xe2x80x83wherein
D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, xe2x80x94CF3 or xe2x80x94(CH2)nxe2x80x94CF3;
B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94N(C1-C6)2, xe2x80x94NH(C1-C6), xe2x80x94Nxe2x80x94C(O)xe2x80x94(C1-C6), xe2x80x94NO2, or by a 5- or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, N or S, such as, for example, morpholino; or a pharmaceutically acceptable salt thereof.
One group of compounds within this invention are those in which the indole or indoline 2-position (R4) is substituted only by hydrogen and the substituents at the other indole or indoline positions are as described above.
Another R3 is xe2x80x94L1xe2x80x94M1, wherein L1 is as defined above, more preferably wherein L1 is a chemical bond, and M1 is the moiety: 
and R9 is as defined in the broad genus above.
Another group of this invention comprises compounds in which R2 and R4 are hydrogen and the groups at R1, R1xe2x80x2, R3, and R5 are as defined above. Within this group are two further preferred groups. In the first, R1 is in the indole or indoline 5 position and in the second R1 is in the indole or indoline 6 position.
In a further preferred group herein, R1 is in the indole or indoline 5-position and is benzyloxy, R2 and R4 are hydrogen and R3 and R4 are as defined above.
Among the more preferred compounds of this invention are those of the following formulae: 
wherein:
R1 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C10 alkyl, preferably xe2x80x94Sxe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, phenyl, xe2x80x94O-phenyl, xe2x80x94S-phenyl, benzyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl or a moiety of the formulae: 
R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
R7 is selected from xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(C1-C6 alkyl)2, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94CF3, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, xe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94Nxe2x80x94(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, quinolyl, (CH2)nphenyl, phenyl,xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, adamantyl, or morpholinyl, xe2x80x94(CH2)n-phenyl-O-phenyl, xe2x80x94(CH2)n-phenyl-CH2-phenyl, xe2x80x94(CH2)nxe2x80x94O-phenyl-CH2-phenyl, xe2x80x94(CH2)n-phenyl-(Oxe2x80x94CH2-phenyl)2, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94CF3,CO2H, or xe2x80x94OH;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from xe2x80x94COOH, xe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94CHxe2x95x90CHxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94tetrazole, 
xe2x80x83or a moiety selected from the formulae xe2x80x94L1xe2x80x94M1;
wherein L1 is a bridging or linking moiety selected from a chemical bond, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94(CH2)nxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SOxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94Oxe2x80x94; xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94, xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94, xe2x80x94C(O)xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94(CH2)nxe2x80x94, xe2x80x94C(Z)xe2x80x94NHxe2x80x94SO2xe2x80x94, or xe2x80x94C(Z)xe2x80x94NHxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94;
n is an integer from 0 to 3
M1 is selected from the group of xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, 
R8, in each appearance, is independently selected from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, 
R9 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1C6 alkyl, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2;
R10 is selected from the group of H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl)2, 
R11 is selected from H, C1-C6 lower alkyl, C1-C6 cycloalkyl, xe2x80x94CF3, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, 
xe2x80x83with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R3, L1, M1, R8, R9, R10, and/or R11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: xe2x80x94C(O)xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NH2, 
n is an integer from 0 to 3;
R4 is selected from H, xe2x80x94CF3, C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, xe2x80x94C1-C6 alkyl-C3-C10 cycloalkyl, xe2x80x94CHO, halogen, or a moiety of the formula xe2x80x94L2xe2x80x94M2:
L2 indicates a linking or bridging group of the formulae xe2x80x94(CH2)nxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94;
M2 is selected from the group of H, C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to pyridine, pyrimidine, piperidine, piperazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH; or
c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, indole, indoline, napthalene, purine, or quinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH;
n is an integer from 0 to 3
R5 is selected from C1-C6 lower alkyl, C1-C6 lower alkoxy, xe2x80x94(CH2)nxe2x80x94C3-C10 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C3-C10 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94C3-C10 cycloalkyl, or the groups of:
a) xe2x80x94(CH2)n-phenyl-O-phenyl, xe2x80x94(CH2)n-phenyl-CH2-phenyl, xe2x80x94(CH2)nxe2x80x94O-phenyl-CH2-phenyl, xe2x80x94(CH2)n-phenyl-(Oxe2x80x94CH2-phenyl)2, xe2x80x94CH2-phenyl-C(O)-benzothiazole or a moiety of the formulae: 
xe2x80x83wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C3xe2x80x94C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl, benzothiazole and pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94CN, xe2x80x94NH2, xe2x80x94NO2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
b) a moiety of the formulae xe2x80x94(CH2)nxe2x80x94A, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94A, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94A, wherein A is the moiety: 
xe2x80x83wherein
D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, xe2x80x94CF3 or xe2x80x94(CH2)nxe2x80x94CF3;
B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2 or xe2x80x94NO2;
or a pharmaceutically acceptable salt thereof.
One group of compounds within this invention are those in which the indole or indoline 2-position (R4) is substituted only by hydrogen and the substituents at the other indole or indoline positions are as described above.
In an another preferred group of this invention R1 is in the indole or indoline 5 or 6 position and is cyclopentylcarboxamide or cyclopentyloxycarbonylamino, R2 and R4 are hydrogen, and R3 and R5 are as defined above.
A further preferred group of this invention consists of R1 and R2 at the indole or indoline 5 and or 6 position and are each selected from the group consisting of C1-C6alkoxy, cyano, sulfonyl and halo, R2 and R4 are hydrogen, and R3 and R5 are as defined above.
Another group of this invention comprises compounds in which R2 and R4 are hydrogen and the groups at R1, R3, and R5 are as defined above. Within this group are two further preferred groups. In the first, R1 is in the indole or indoline 5 position and in the second R1 is in the indole or indoline 6 position.
In a further preferred group herein, R1 is in the indole or indoline 5-position and is benzyloxy, R2 and R4 are hydrogen and R3 and R5 are as defined above.
A preferred group of compounds of this invention have the following formulae: 
wherein:
R1 is selected form H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, CN, phenyl, xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl or a moiety of the formulae: 
R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94CF3, or xe2x80x94OH;
R7 is selected from xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(C1-C6 alkyl)2, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94CF3, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, xe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94Nxe2x80x94(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, quinolyl, (CH2)nphenyl, phenyl,xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, adamantyl, or morpholinyl, xe2x80x94(CH2)n-phenyl-O-phenyl, xe2x80x94(CH2)n-phenyl-CH2-phenyl, xe2x80x94(CH2)nxe2x80x94O-phenyl-CH2-phenyl, xe2x80x94(CH2)n-phenyl-(Oxe2x80x94CH2-phenyl)2, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1xe2x80x94C6 alkoxy, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94CF3,CO2H, or xe2x80x94OH;
R2 is selected from H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OH, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from xe2x80x94COOH, xe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94CHxe2x95x90CHxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94tetrazole, 
xe2x80x83or a moiety selected from the formulae xe2x80x94L1xe2x80x94M1;
wherein L1 is a bridging or linking moiety selected from a chemical bond, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94,xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SOxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94Oxe2x80x94;
xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94, xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94(CH2)nxe2x80x94xe2x80x94C(O)xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94, xe2x80x94C(O)xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94(CH2)nxe2x80x94, xe2x80x94C(Z)xe2x80x94NHxe2x80x94SO2xe2x80x94, or xe2x80x94C(Z)xe2x80x94NHxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94;
n is an integer from 0 to 3
M1 is selected from the group of xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, 
R8, in each appearance, is independently selected from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, 
R9 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl)2;
R10 is selected from the group of H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl)2, 
R11 is selected from H, C1-C6 lower alkyl, C1-C6 cycloalkyl, xe2x80x94CF3, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, 
xe2x80x83with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R3, L1, M1, R8, R9, R10, and/or R11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: xe2x80x94C(O)xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NH2, 
n is an integer from 0 to 3;
R4 is selected from H, xe2x80x94CF3, C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, xe2x80x94C1-C6 alkyl-C3-C10 cycloalkyl, xe2x80x94CHO, halogen, or a moiety of the formula xe2x80x94L2xe2x80x94M2:
L2 indicates a linking or bridging group of the formulae xe2x80x94(CH2)nxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94;
M2 is selected from:
a) H, the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH; or
d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH;
R5 is selected from C1-C6 lower alkyl, C1-C6 lower alkoxy, xe2x80x94(CH2)nxe2x80x94C3-C5 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C1-C5 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94C3-C5 cycloalkyl, or the groups of:
a) xe2x80x94(CH2)n-phenyl-O-phenyl, xe2x80x94(CH2)n-phenyl-CH2-phenyl, xe2x80x94(CH2)nxe2x80x94O-phenyl-CH2-phenyl, xe2x80x94(CH2)n-phenyl-(Oxe2x80x94CH2-phenyl)2, xe2x80x94CH2-phenyl-C(O)-benzothiazole or a moiety of the formulae: 
xe2x80x83wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C3-C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl benzothiazole or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
b) a moiety of the formulae xe2x80x94(CH2)nxe2x80x94A, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94A, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94A, wherein A is the moiety: 
xe2x80x83wherein
D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, xe2x80x94(CH2)nxe2x80x94CF3or xe2x80x94CF3;
B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2 or xe2x80x94NO2;
or a pharmaceutically acceptable salt thereof.
A preferred group among the compounds above are those in which the R1 substitution is at the indole or indoline ring""s 5-position and the other substituents are as defined above.
Another preferred group of this invention are those of the formulae: 
wherein:
R1 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C10 alkyl, preferably xe2x80x94Sxe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94HN(C1-C6), xe2x80x94N(C1-C6)2, phenyl, xe2x80x94O-phenyl, xe2x80x94S-phenyl, benzyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
or a moiety of the formulae: 
R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94CF3, or xe2x80x94OH;
R7 is selected from xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(C1-C6 alkyl)2, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94CF3, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, xe2x80x94NHxe2x80x94(C1 -C6 alkyl), xe2x80x94Nxe2x80x94(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, quinolyl, (CH2)nphenyl, phenyl,xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, adamantyl, or morpholinyl, xe2x80x94(CH2)n-phenyl-O-phenyl, xe2x80x94(CH2)n-phenyl-CH2-phenyl, xe2x80x94(CH2)nxe2x80x94O-phenyl-CH2-phenyl, xe2x80x94(CH2)n-phenyl-(Oxe2x80x94CH2-phenyl)2, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94CF3,CO2H, or xe2x80x94OH;
R2 is selected from H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OH, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from xe2x80x94COOH, xe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94CHxe2x95x90CHxe2x80x94COOH, xe2x80x94(CH2)n-tetrazole, 
xe2x80x83or a moiety selected from the formulae xe2x80x94L1xe2x80x94M1;
wherein L1 is a bridging or linking moiety selected from a chemical bond, , xe2x80x94(CH2)nxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94,xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SOxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94Oxe2x80x94;
n is an integer from 0 to 3
M1 is selected from the group of xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, 
R8, in each appearance, is independently selected from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NH2, 
n is an integer from 0 to 3;
R9 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl)2;
R4 is selected from H, xe2x80x94CF3, C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, xe2x80x94C1-C6 alkyl-C3-C10 cycloalkyl, xe2x80x94CHO, halogen, or a moiety of the formula xe2x80x94L2xe2x80x94M2:
L2 indicates a linking or bridging group of the formulae xe2x80x94(CH2)nxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94;
M2 is selected from:
a) H, the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH; or
d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH;
R5 is selected from C1-C6 lower alkyl, C1-C6 lower alkoxy, xe2x80x94(CH2)nxe2x80x94C3-C5 cycloalkyl or xe2x80x94(CH2)nxe2x80x94A, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94A, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94A wherein A is selected from: 
D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or xe2x80x94CF3;
R12 is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or xe2x80x94CF3;
or a pharmaceutically acceptable salt thereof.
Other compounds of this invention have the following formulae: 
wherein:
R1 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C10 alkyl, preferably xe2x80x94Sxe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94HN(C1-C6), xe2x80x94N(C1-C6)2, phenyl, xe2x80x94O-phenyl, xe2x80x94S-phenyl, benzyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH; 
R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94CF3, or xe2x80x94OH;
R7 is selected from xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(C1-C6 alkyl)2, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94CF3, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, xe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94Nxe2x80x94(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, quinolyl, (CH2)nphenyl, phenyl,xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, adamantyl, or morpholinyl, xe2x80x94(CH2)n-phenyl-O-phenyl, xe2x80x94(CH2)n-phenyl-CH2-phenyl, xe2x80x94(CH2)nxe2x80x94O-phenyl-CH2-phenyl, xe2x80x94(CH2)n-phenyl-(Oxe2x80x94CH2-phenyl)2, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94CF3,CO2H, or xe2x80x94OH;
R2 is selected from H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OH, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from xe2x80x94COOH, xe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, (CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94tetrazole, 
xe2x80x83or a moiety selected from the formulae xe2x80x94L1xe2x80x94M1 or L2M2;
L1 is a bridging or linking moiety selected from a chemical bond, xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94,xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SOxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94Oxe2x80x94;
M1 is selected from the group of xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, 
L2 is a bridging or linking moiety selected from a chemical bond xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94,xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SOxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94Oxe2x80x94; xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94, xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94, xe2x80x94C(O)xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94(CH2)nxe2x80x94, xe2x80x94C(Z)xe2x80x94NHxe2x80x94SO2xe2x80x94, or xe2x80x94C(Z)xe2x80x94NHxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94;
M2 is the moiety 
R8, in each appearance, is independently selected from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NH2 
R9, is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl)2;
R10 is selected from the group of H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl)2, 
xe2x80x83with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R3, L1, M1, L2, M2, R8, R9, R10, shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: xe2x80x94C(O)xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NH2 
n is an integer from 0 to 3;
R4 is selected from H, xe2x80x94CF3, C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, xe2x80x94C1-C6 alkyl, xe2x80x94C3-C10 cycloalkyl, xe2x80x94CHO, halogen, (CH2)nC(O)NH2, or a moiety of the formula xe2x80x94L3xe2x80x94M3:
L3 indicates a linking or bridging group of the formulae xe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, C(O)C(O)X, xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(CH2)n;
M3 is selected from:
a) H, the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
R5 is selected from the groups of:
a) a moiety of the formulae xe2x80x94(CH2)nxe2x80x94A, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94A, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94A, wherein A is the moiety: 
xe2x80x83wherein
D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, xe2x80x94CF3 or xe2x80x94(CH2)nxe2x80x94CF3;
B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2 or xe2x80x94NO2;
or a pharmaceutically acceptable salt thereof.
Another preferred group of this invention are those of the formulae: 
wherein:
R1 and R1xe2x80x2 are independently selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C10 alkyl, preferably xe2x80x94Sxe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94HN(C1-C6), xe2x80x94N(C1-C6)2, phenyl, xe2x80x94O-phenyl, xe2x80x94S-phenyl, benzyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is a moiety selected from the groups of: 
xe2x80x83wherein
L1 is a bridging or linking moiety selected from a chemical bond, xe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94Oxe2x80x94(CH2)nxe2x80x2xe2x80x94,xe2x80x94(CH2)nxe2x80x2xe2x80x94Sxe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94SOxe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94SO2xe2x80x94(CH2)nxe2x80x2xe2x80x94, or xe2x80x94(CH2)nxe2x80x2xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x2xe2x80x94Oxe2x80x94;
where nxe2x80x2 is an integer from 0 to 5;
R9 is selected from halogen, xe2x80x94CF3, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2,
n in each instance is independently selected as an integer from 0 to 3;
R4 is selected from H, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94(CH2)nxe2x80x94OH, (CH2)nC(O)NH2, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(C1-C6 alkyl), xe2x80x94(CH2)nxe2x80x94Oxe2x80x94CH2-phenyl, xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(C1-C6 alkyl), xe2x80x94(CH2)nxe2x80x94Nxe2x80x94CH2-phenyl, the phenyl rings of which are optionally substituted by 1 or 2 groups selected from H, halogen, xe2x80x94CF3 or xe2x80x94C1-C6 alkyl;
n is an integer from 0-3
R5 is selected from C1-C6 lower alkyl, C1-C6 lower alkoxy, xe2x80x94(CH2)nxe2x80x94C3-C5 cycloalkyl or xe2x80x94(CH2)nxe2x80x94A, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94A, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94A wherein A is selected from: 
D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or xe2x80x94CF3;
R12 is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or xe2x80x94CF3;
or a pharmaceutically acceptable salt thereof.
The compounds of this invention have the following formulae: 
wherein:
R1 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C10 alkyl, preferably xe2x80x94Sxe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94HN(C1-C6), xe2x80x94N(C1-C6)2, phenyl, xe2x80x94O-phenyl, xe2x80x94S-phenyl, benzyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is a moiety selected from the groups of: 
xe2x80x83wherein
L1 is a bridging or linking moiety selected from a chemical bond, xe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94Oxe2x80x94(CH2)nxe2x80x2xe2x80x94,xe2x80x94(CH2)nxe2x80x2xe2x80x94Sxe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94SOxe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94SO2xe2x80x94(CH2)nxe2x80x2xe2x80x94, or xe2x80x94(CH2)nxe2x80x2xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x2xe2x80x94Oxe2x80x94;
where nxe2x80x2 is an integer from 0 to 5;
R9 is selected from halogen, xe2x80x94CF3, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2,
n in each instance is independently selected as an integer from 0 to 3 or a pharmaceutically acceptable salt thereof
R4 is selected from H, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94(CH2)nxe2x80x94OH, (CH2)nC(O)NH2, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(C1-C6 alkyl), xe2x80x94(CH2)nxe2x80x94Oxe2x80x94CH2-phenyl, xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(C1-C6 alkyl), xe2x80x94(CH2)nxe2x80x94Nxe2x80x94CH2-phenyl, the phenyl rings of which are optionally substituted by 1 or 2 groups selected from H, halogen, xe2x80x94CF3 or xe2x80x94C1-C6 alkyl;
n is an integer from 0-3
R5 is a moiety of the formulae xe2x80x94(CH2)nxe2x80x94A, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94A, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94A, wherein A is the moiety: 
xe2x80x83wherein
D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or xe2x80x94CF3;
B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, or xe2x80x94NO2;
or a pharmaceutically acceptable salt thereof.
Yet another preferred group herein are the compounds of the formulae: 
wherein:
R1 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94HN(C1-C6), xe2x80x94N(C1-C6)2, phenyl, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, , xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2-C1-C6 alkyl;
R3 is a moiety selected from the groups of: 
xe2x80x83wherein
L1 is a bridging or linking moiety selected from a chemical bond, xe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94Oxe2x80x94(CH2)nxe2x80x2xe2x80x94,xe2x80x94(CH2)nxe2x80x2xe2x80x94Sxe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94SOxe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94SO2xe2x80x94(CH2)nxe2x80x2xe2x80x94, or xe2x80x94(CH2)nxe2x80x2xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x2xe2x80x94Oxe2x80x94;
nxe2x80x2 in each instance is independently selected as an integer from 0 to 5;
R4 is selected from H, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94(CH2)nxe2x80x94OH, (CH2)nC(O)NH2, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(C1-C6 alkyl), xe2x80x94(CH2)nxe2x80x94Oxe2x80x94CH2-phenyl, xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(C1-C6 alkyl), xe2x80x94(CH2)nxe2x80x94Nxe2x80x94CH2-phenyl, the phenyl rings of which are optionally substituted by 1 or 2 groups selected from H, halogen, xe2x80x94CF3 or xe2x80x94C1-C6 alkyl;
n is an integer from 0-3
or a pharmaceutically acceptable salt thereof.
As used herein, the terms xe2x80x9carylxe2x80x9d and xe2x80x9csubstituted arylxe2x80x9d are understood to include monocyclic, particularly including five- and six-membered monocyclic, aromatic and heteroaromatic ring moieties and bicyclic aromatic and heteroaromatic ring moieties, particularly including those having from 9 to 10 ring atoms. Among these aryl groups are understood to be phenyl rings, including those found in phenoxy, benzyl, benzyloxy, biphenyl and other such moieties. The aryl and heteroaryl groups of this invention also include the following:
a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, or oxathiazole; or
b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine; or
c) a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine.
The xe2x80x9csubstituted arylxe2x80x9d groups of this invention include such aryl moieties being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94COOH or esters thereof, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH or combinations thereof, such as xe2x80x94CH2CF3, xe2x80x94NH(CH3), etc.
The integers depicted by the variable n are in each appearance independently an integer from 0 to 3, preferably 0 to 2, more preferably 0 to 1. It will be understood the appearance of n in any instance is not definitive or limiting of the integer which may be indicated by n elsewhere within the definition of the present invention. For instance, each of the integers indicated by n in the moiety xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94 may be selected from 0, 1, 2 or 3.
A preferred subset of these groups, optionally substituted as just described, include moieties formed from benzene, pyridine, napthylene or quinoline rings. A further preferred group includes those of furan, pyrrole, thiophene, pyrimidine, and morpholine rings. A preferred group of bicyclic aromatic groups includes benzofuran, indole, napthalene, and quinoline rings.
The alkyl, alkenyl and alkinyl groups referred to herein indicate such groups having from 1 to 10, preferably 1 to 6 carbon atoms, and may be straight, branched or cyclic. Unless indicated otherwise, it is preferred that these groups be straight or branched. Alkoxy groups herein indicate alkyl groups, as just defined, bridged to the relevant moiety by an oxygen atom.
Halogens herein are understood to include F, Cl, Br and I. As used herein, xe2x80x9cphospholipase enzyme activityxe2x80x9d means positive activity in an assay for metabolism of phospholipids (preferably one of the assays described in Example 116 below). A compound has xe2x80x9cphospholipase enzyme inhibiting activityxe2x80x9d when it inhibits the activity of a phospholipase (preferably cPLA2) in any available assay (preferably an assay described below in Example 116 or Example 117) for enzyme activity. In preferred embodiments, a compound has (1) an IC50 value of less than about 25 xcexcM, preferably less than about 6 xcexcM, in the LysoPC assay; (2) an IC50 value of less than about 50 xcexcM in the vesicle assay; (3) an IC50 value of less than about 1 xcexcM in the PMN assay; (4) an IC50 value of less than about 15 xcexcM in the Coumarine assay; and/or (5) measurable activity (preferably at least about 5% reduction in edema, more preferably at least about 10% reduction, more preferably at least about 15%, most preferably 20-30%) in the rat carrageenanxe2x80x94induced footpad edema test.
Compounds of the present invention are useful for inhibiting phospholipase enzyme (preferably cPLA2) activity and, therefore, are useful in xe2x80x9ctreatingxe2x80x9d (i.e., treating, preventing or ameliorating) inflammatory or inflammation-related responses or conditions (e.g., rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease, and other diseases mediated by prostaglandins, leukotrienes or PAF) and other conditions, such as osteoporosis, colitis, myelogenous leukemia, diabetes, wasting and atherosclerosis.
The present invention encompasses both pharmaceutical compositions and therapeutic methods of treatment or use which employ compounds of the present invention.
Compounds of the present invention may be used in a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. Such a composition may also contain (in addition to a compound or compounds of the present invention and a carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The term xe2x80x9cpharmaceutically acceptablexe2x80x9d means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s). The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition may further contain other anti-inflammatory agents. Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with compounds of the present invention, or to minimize side effects caused by the compound of the present invention.
The pharmaceutical composition of the invention may be in the form of a liposome in which compounds of the present invention are combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution. Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Pat. Nos. 4,235,871; 4,501,728; 4,837,028; and 4,737,323, all of which are incorporated herein by reference.
As used herein, the terms xe2x80x9cpharmaceutically effective amountxe2x80x9d or xe2x80x9ctherapeutically effective amountxe2x80x9d means the total amount of each active component of the pharmaceutical composition or method that is sufficient to show a meaningful patient benefit, i.e., treatment, healing, prevention or amelioration of an inflammatory response or condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
In practicing the method of treatment or use of the present invention, a therapeutically effective amount of a compound of the present invention is administered to a mammal having a condition to be treated. Compounds of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors. When co-administered with one or more other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors, compounds of the present invention may be administered either simultaneously with the other anti-inflammatory agent(s), cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering compounds of the present invention in combination with other anti-inflammatory agent(s), cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors.
Administration of compounds of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, or cutaneous, subcutaneous, or intravenous injection.
When a therapeutically effective amount of compounds of the present invention is administered orally, compounds of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an adjuvant. The tablet, capsule, and powder contain from about 5 to 95% compound of the present invention, and preferably from about 25 to 90% compound of the present invention. When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added. The liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains from about 0.5 to 90% by weight of compound of the present invention, and preferably from about 1 to 50% compound of the present invention.
When a therapeutically effective amount of compounds of the present invention is administered by intravenous, cutaneous or subcutaneous injection, compounds of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable protein solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to compounds of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer""s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer""s Injection, or other vehicle as known in the art. The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art.
The amount of compound(s) of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone. Ultimately, the attending physician will decide the amount of compound of the present invention with which to treat each individual patient. Initially, the attending physician will administer low doses of compound of the present invention and observe the patient""s response. Larger doses of compounds of the present invention may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.1 xcexcg to about 100 mg (preferably about 0.1 mg to about 50 mg, more preferably about 1 mg to about 2 mg) of compound of the present invention per kg body weight.
The duration of intravenous therapy using the pharmaceutical composition of the present invention will vary, depending on the severity of the disease being treated and the condition and potential idiosyncratic response of each individual patient. It is contemplated that the duration of each application of the compounds of the present invention will be in the range of 12 to 24 hours of continuous intravenous administration. Ultimately the attending physician will decide on the appropriate duration of intravenous therapy using the pharmaceutical composition of the present invention.